A protein structural study based on the centrality analysis of protein sequence feature networks.
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ABSTRACT:
SUBMITTER: Wan X
PROVIDER: S-EPMC8006989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn the pharmaceutical industry, competing for few validated drug targets there is a drive to identify new ways of therapeutic intervention. Here, we attempted to define guidelines to evaluate a target's 'fitness' based on its node characteristics within annotated protein functional networks to complement contingent therapeutic hypotheses.ResultsWe observed that targets of approved, selective small molecule drugs exhibit high node centrality within protein networks relative to a broader set of investigational targets spanning various development stages. Targets of approved drugs also exhibit higher centrality than other proteins within their respective functional class. These findings expand on previous reports of drug targets' network centrality by suggesting some centrality metrics such as low topological coefficient as inherent characteristics of a 'good' target, relative to other exploratory targets and regardless of its functional class. These centrality metrics could thus be indicators of an individual protein's 'fitness' as potential drug target. Correlations between protein nodes' network centrality and number of associated publications underscored the possibility of knowledge bias as an inherent limitation to such predictions.ConclusionsDespite some entanglement with knowledge bias, like structure-oriented 'druggability' assessments of new protein targets, centrality metrics could assist early pharmaceutical discovery teams in evaluating potential targets with limited experimental proof of concept and help allocate resources for an effective drug discovery pipeline.
| S-EPMC8555226 | biostudies-literature
Project description:Numerous centrality measures have been developed to quantify the importances of nodes in time-independent networks, and many of them can be expressed as the leading eigenvector of some matrix. With the increasing availability of network data that changes in time, it is important to extend such eigenvector-based centrality measures to time-dependent networks. In this paper, we introduce a principled generalization of network centrality measures that is valid for any eigenvector-based centrality. We consider a temporal network with N nodes as a sequence of T layers that describe the network during different time windows, and we couple centrality matrices for the layers into a supra-centrality matrix of size NT × NT whose dominant eigenvector gives the centrality of each node i at each time t. We refer to this eigenvector and its components as a joint centrality, as it reflects the importances of both the node i and the time layer t. We also introduce the concepts of marginal and conditional centralities, which facilitate the study of centrality trajectories over time. We find that the strength of coupling between layers is important for determining multiscale properties of centrality, such as localization phenomena and the time scale of centrality changes. In the strong-coupling regime, we derive expressions for time-averaged centralities, which are given by the zeroth-order terms of a singular perturbation expansion. We also study first-order terms to obtain first-order-mover scores, which concisely describe the magnitude of nodes' centrality changes over time. As examples, we apply our method to three empirical temporal networks: the United States Ph.D. exchange in mathematics, costarring relationships among top-billed actors during the Golden Age of Hollywood, and citations of decisions from the United States Supreme Court.
| S-EPMC5643020 | biostudies-literature
Project description:Proteins are diverse with their sequences, structures and functions, it is important to study the relations between the sequences, structures and functions. In this paper, we conduct a study that surveying the relations between the protein sequences and their structures. In this study, we use the natural vector (NV) and the averaged property factor (APF) features to represent protein sequences into feature vectors, and use the multi-class MSE and the convex hull methods to separate proteins of different structural classes into different regions. We found that proteins from different structural classes are separable by hyper-planes and convex hulls in the natural vector feature space, where the feature vectors of different structural classes are separated into disjoint regions or convex hulls in the high dimensional feature spaces. The natural vector outperforms the averaged property factor method in identifying the structures, and the convex hull method outperforms the multi-class MSE in separating the feature points. These outcomes convince the strong connections between the protein sequences and their structures, and may imply that the amino acids composition and their sequence arrangements represented by the natural vectors have greater influences to the structures than the averaged physical property factors of the amino acids.
| S-EPMC6927603 | biostudies-literature
Project description:Numerous centrality measures have been introduced to identify "central" nodes in large networks. The availability of a wide range of measures for ranking influential nodes leaves the user to decide which measure may best suit the analysis of a given network. The choice of a suitable measure is furthermore complicated by the impact of the network topology on ranking influential nodes by centrality measures. To approach this problem systematically, we examined the centrality profile of nodes of yeast protein-protein interaction networks (PPINs) in order to detect which centrality measure is succeeding in predicting influential proteins. We studied how different topological network features are reflected in a large set of commonly used centrality measures.We used yeast PPINs to compare 27 common of centrality measures. The measures characterize and assort influential nodes of the networks. We applied principal component analysis (PCA) and hierarchical clustering and found that the most informative measures depend on the network's topology. Interestingly, some measures had a high level of contribution in comparison to others in all PPINs, namely Latora closeness, Decay, Lin, Freeman closeness, Diffusion, Residual closeness and Average distance centralities.The choice of a suitable set of centrality measures is crucial for inferring important functional properties of a network. We concluded that undertaking data reduction using unsupervised machine learning methods helps to choose appropriate variables (centrality measures). Hence, we proposed identifying the contribution proportions of the centrality measures with PCA as a prerequisite step of network analysis before inferring functional consequences, e.g., essentiality of a node.
| S-EPMC6069823 | biostudies-other
Project description:Network representations of systems from various scientific and societal domains are neither completely random nor fully regular, but instead appear to contain recurring structural features. These features tend to be shared by networks belonging to the same broad class, such as the class of social networks or the class of biological networks. Within each such class, networks describing similar systems tend to have similar features. This occurs presumably because networks representing similar systems would be expected to be generated by a shared set of domain specific mechanisms, and it should therefore be possible to classify networks based on their features at various structural levels. Here we describe and demonstrate a new hybrid approach that combines manual selection of network features of potential interest with existing automated classification methods. In particular, selecting well-known network features that have been studied extensively in social network analysis and network science literature, and then classifying networks on the basis of these features using methods such as random forest, which is known to handle the type of feature collinearity that arises in this setting, we find that our approach is able to achieve both higher accuracy and greater interpretability in shorter computation time than other methods.
| S-EPMC6980283 | biostudies-literature
Project description:Type 1 diabetes (T1D) occurs as a consequence of an autoimmune attack against pancreatic β- cells. Due to a lack of a clear understanding of the T1D pathogenesis, the identification of effective therapies for T1D is the active area in the research. The study purpose was to prioritize potential drugs and targets in T1D via systems biology approach. Gene expression data of peripheral blood mononuclear cells (PBMCs) and pancreatic β-cells in T1D were analyzed and differential expressed genes were integrated with protein-protein interactions (PPI) data. Multiple topological centrality parameters of extracted query-query PPI (QQPPI) networks were calculated and the interaction of more central proteins with drugs was investigated. Molecular docking was performed to further predict the interactions between drugs and the binding sites of targets. Central proteins were identified by the analysis of PBMC (MYC, ERBB2, PSMA1, ABL1 and HSP90AA1) and pancreatic β-cells (HSP90AB1, ESR1, RELA, RAC1, NFKB1, NFKB2, IKBKE, ARRB2 and SRC) QQPPI networks. Thirteen drugs which targeted eight central proteins were identified by further analysis of drug-target interactions. Some drugs which investigated for diabetes treatment in the experimental models of T1D were prioritized by literature verification, including melatonin, resveratrol, lapatinib, geldanamycin, eugenol and fostaminib. Finally, according on molecular docking analysis, lapatinib-ERBB2 and eugenol-ESR1 exhibited highest and lowest binding energy, respectively. This study presented promising results for the prioritization of potential drug-targets which might facilitate T1D targeted therapy and its drug discovery process more effectively.
| S-EPMC8019861 | biostudies-literature
Project description:Topological centrality is a significant measure for characterising the relative importance of a node in a complex network. For directed networks that model dynamic processes, however, it is of more practical importance to quantify a vertex's ability to dominate (control or observe) the state of other vertices. In this paper, based on the determination of controllable and observable subspaces under the global minimum-cost condition, we introduce a novel direction-specific index, domination centrality, to assess the intervention capabilities of vertices in a directed network. Statistical studies demonstrate that the domination centrality is, to a great extent, encoded by the underlying network's degree distribution and that most network positions through which one can intervene in a system are vertices with high domination centrality rather than network hubs. To analyse the interaction and functional dependence between vertices when they are used to dominate a network, we define the domination similarity and detect significant functional modules in glossary and metabolic networks through clustering analysis. The experimental results provide strong evidence that our indices are effective and practical in accurately depicting the structure of directed networks.
| S-EPMC4066263 | biostudies-other
Project description:Proteins within a molecular network are expected to be subject to different selective pressures depending on their relative hierarchical positions. However, it is not obvious what genes within a network should be more likely to evolve under positive selection. On one hand, only mutations at genes with a relatively high degree of control over adaptive phenotypes (such as those encoding highly connected proteins) are expected to be "seen" by natural selection. On the other hand, a high degree of pleiotropy at these genes is expected to hinder adaptation. Previous analyses of the human protein-protein interaction network have shown that genes under long-term, recurrent positive selection (as inferred from interspecific comparisons) tend to act at the periphery of the network. It is unknown, however, whether these trends apply to other organisms. Here, we show that long-term positive selection has preferentially targeted the periphery of the yeast interactome. Conversely, in flies, genes under positive selection encode significantly more connected and central proteins. These observations are not due to covariation of genes' adaptability and centrality with confounding factors. Therefore, the distribution of proteins encoded by genes under recurrent positive selection across protein-protein interaction networks varies from one species to another.
| S-EPMC4826914 | biostudies-literature
Project description:The determination of node centrality is a fundamental topic in social network studies. As an addition to established metrics, which identify central nodes based on their brokerage power, the number and weight of their connections, and the ability to quickly reach all other nodes, we introduce five new measures of Distinctiveness Centrality. These new metrics attribute a higher score to nodes keeping a connection with the network periphery. They penalize links to highly-connected nodes and serve the identification of social actors with more distinctive network ties. We discuss some possible applications and properties of these newly introduced metrics, such as their upper and lower bounds. Distinctiveness centrality provides a viewpoint of centrality alternative to that of established metrics.
| S-EPMC7244137 | biostudies-literature
Project description:Protein networks, describing physical interactions as well as functional associations between proteins, have been unravelled for many organisms in the recent past. Databases such as the STRING provide excellent resources for the analysis of such networks. In this contribution, we revisit the organisation of protein networks, particularly the centrality-lethality hypothesis, which hypothesises that nodes with higher centrality in a network are more likely to produce lethal phenotypes on removal, compared to nodes with lower centrality. We consider the protein networks of a diverse set of 20 organisms, with essentiality information available in the Database of Essential Genes and assess the relationship between centrality measures and lethality. For each of these organisms, we obtained networks of high-confidence interactions from the STRING database, and computed network parameters such as degree, betweenness centrality, closeness centrality and pairwise disconnectivity indices. We observe that the networks considered here are predominantly disassortative. Further, we observe that essential nodes in a network have a significantly higher average degree and betweenness centrality, compared to the network average. Most previous studies have evaluated the centrality-lethality hypothesis for Saccharomyces cerevisiae and Escherichia coli; we here observe that the centrality-lethality hypothesis hold goods for a large number of organisms, with certain limitations. Betweenness centrality may also be a useful measure to identify essential nodes, but measures like closeness centrality and pairwise disconnectivity are not significantly higher for essential nodes.
| S-EPMC3933631 | biostudies-literature